Regulation of T-cell immune exhaustion and cancer immunotherapy

In chronic infectious diseases and cancer, CD8⁺ T cells specific for viral and/or tumor antigens undergo repeated T cell receptor (TCR) stimulation due to the persistence of pathogens or cancer cells, gradually losing their ability to secrete interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ-(IFN-γ). These CD8⁺ T cells are finally eliminated by apoptosis, a process referred to as immune exhaustion. The worsening immune function is accompanied by phenotypic changes in CD8⁺ T cells, for example, by changes in the expression of exhaustion markers such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T cell immunoglobulin mucin 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3). The exhaustion molecules on CD8⁺ T cells interact with their respective ligands and induce negative signals in activated T cells, leading to CD8⁺ T cell dysfunction. In 2013, the combined use of anti-PD-1 and anti-CTLA-4 antibodies was shown to induce extraordinary anti-tumor effects in patients with advanced melanoma. The regulation of exhausted CD8⁺ T cells has now emerged as a promising therapy to treat cancer.